1,4-disubstituted piperazines

ABSTRACT

The present invention relates to 1,4-disubstituted piperazines of the general formula ##STR1## wherein X, Y, Z, R 1 , R 2  and r are as defined in the detailed part of the present description or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation as well as their use for the treatment of indications caused by or related to the secretion and circulation of insulin antagonising peptides, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 08/943,726filed Oct. 3, 1997 and claims priority under 35 U.S.C. 119 of Danishapplication 1090/96 filed Oct. 4, 1996, the contents of which are fullyincorporated herein by reference.

FIELD OF INVENTION

The present invention relates to novel N-substituted azaheterocycliccompounds in which a substituted alkyl chain forms part of theN-substituent or salts thereof, to methods for their preparation, tocompositions containing them, to the use of the compounds for preparingcompositions for the clinical treatment of painful, hyperalgesic and/orinflammatory conditions in which C-fibres play a pathophysiological roleby eliciting neurogenic pain or inflammation, and to methods of treatingsaid painful, hyperalgesic and/or inflammatory conditions. The inventionalso relates to the use of the present compounds for reducing bloodglucose and/or inhibit the secretion, circulation or effect of insulinantagonising peptides like CGRP or amylin, the present compounds beingknown to interfere with neuropeptide containing C-fibres. Hence thepresent compounds can be used in the treatment of insulin resistance innon-insulin-dependent diabetes mellitus (NIDDM) in order to improve theglucose tolerance as well as ageing-associated obesity.

BACKGROUND OF INVENTION

The nervous system exerts a profound effect on the inflammatoryresponse. Antidromic stimulation of sensory nerves results in localisedvasodilation and increased vascular permeability (Janecso et al. Br. J.Pharmacol. 1967, 31, 138-151) and a similar response is observedfollowing injection of peptides known to be present in sensory nerves.From this and other data it is postulated that peptides released fromsensory nerve endings mediate many inflammatory responses in tissueslike skin, joint, urinary tract, eye, meninges, gastrointestinal andrespiratory tracts. Hence inhibition of sensory nerve peptide releaseand/or activity, may be useful in treatment of, for example arthritis,dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlelitis,glaucoma, gastrointestinal diseases or migraine.

Further, the potent effects of CGRP on skeletal muscle glycogen synthaseactivity and muscle glucose metabolism, together with the notion thatthis peptide is released from the neuromuscular junction by nerveexcitation, suggest that CGRP may play a physiological role in skeletalmuscle glucose metabolism by directing the phosphorylated glucose awayfrom glycogen storage and into the glycolytic and oxidative pathways(Rossetti et al. Am. J. Physiol. 264, E1-E10, 1993). This peptide mayrepresent an important physiological modulator of intracellular glucosetrafficking in physiological conditions, such as exercise, and may alsocontribute to the decreased insulin action and skeletal muscle glycogensynthase in pathophysiological conditions like NIDDM orageing-associated obesity (Melnyk et al. Obesity Res. 3, 337-344, 1995)where circulating plasma levels of CGRP are markedly increased. Henceinhibition of release and/or activity of the neuropeptide CGRP may beuseful in the treatment of insulin resistance related to type 2 diabetesor ageing.

In U.S. Pat. No. 4,383,999 and U.S. Pat. No. 4,514,414 and in EP 236342as well as in EP 231996 some derivatives ofN-(4,4-disubstituted-3-butenyl)azaheterocyclic carboxylic acids areclaimed as inhibitors of GABA uptake. In EP 342635 and EP 374801,N-substituted azaheterocyclic carboxylic acids in which an oxime ethergroup and vinyl ether group forms part of the N-substituent respectivelyare claimed as inhibitors of GABA uptake. Further, in WO 9107389 and WO9220658, N-substituted azacyclic carboxylic acids are claimed as GABAuptake inhibitors. EP 221572 claims that1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the general formula I,wherein X, Y, Z, M₁, M₂, R¹ through R¹², r and m are as defined in thedetailed part of the present description.

The present compounds are useful for the treatment, prevention,elimination, alleviation or amelioration of an indication related to allpainful, hyperalgesic and/or inflammatory conditions in which C-fibresplay a pathophysiological role, e.g. neurogenic pain, inflammation,migraine, neuropathy, itching and rheumatoid arthritis, as well asindications caused by or related to the secretion and circulation ofinsulin antagonising peptides, e.g. non-insulin-dependent diabetesmellitus (NIDDM) and ageing-associated obesity.

In another aspect, the present invention includes within its scopepharmaceutical compositions comprising, as an active ingredient, atleast one of the compounds of the general formula I or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent.

In another aspect of the present invention there is provided a method oftreating painful, hyperalgesic and/or inflammatory conditions in whichC-fibres play a pathophysiological role, e.g. neurogenic pain,inflammation, migraine, neuropathy, itching and rheumatoid arthritis, aswell as a method of treating indications caused by or related to thesecretion and circulation of insulin antagonising peptides like CGRP oramylin, e.g. non-insulin-dependent diabetes mellitus (NIDDM) andageing-associated obesity. The method of treating may be described asthe treatment of one of the above indications in a subject in needthereof, which comprises the step of administering to the said subject aneurologically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof.

A further aspect of the invention relates to the use of a compound ofthe present invention for the preparation of a pharmaceuticalcomposition for the treatment of all painful, hyperalgesic and/orinflammatory conditions in which C-fibres play a pathophysiologicalrole, e.g. neurogenic pain, inflammation, migraine, neuropathy, itchingand rheumatoid arthritis, as well as for the treatment of indicationscaused by or related to the secretion and circulation of insulinantagonising peptides, e.g. non-insulin-dependent diabetes mellitus(NIDDM) and ageing-associated obesity.

Further objects will become apparent from the following description.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to novel 1,4-disubstitutedpiperazines of formula I: ##STR2## wherein R¹ and R² independently arehydrogen, halogen, trifluoromethyl, hydroxy, C₁₋₆ -alkyl or C₁₋₆-alkoxy; and

X is ortho-phenylene, --O--, --S--, --C(R⁶ R⁷)--, --CH₂ CH₂ --,--CH═CH--CH₂ --, --CH₂ --CH═CH--, --CH₂ --(C═O)--, --(C═O)--CH₂ --,--CH₂ CH₂ CH₂ --, --CH═CH--, --N(R⁸)--(C═O)--, --(C═O)--N(R⁸)--,--O--CH₂ --O--, --OCH₂ O--, --S--CH₂ --, --CH₂ --S--, --(CH₂)N(R⁸)--,--N(R⁸)(CH₂)--, --N(CH₃)SO₂ --, --SO₂ N(CH₃)--, CH(R¹⁰)CH₂ --, --CH₂CH(R¹⁰), --(C═O)--, --N(R⁹)-- or --(S═O)-- wherein R⁶, R⁷, R⁸ and R⁹independently are hydrogen or C₁₋₆ -alkyl; and wherein R¹⁰ is C₁₋₆-alkyl or phenyl; and

Y is >N--CH₂ --, >CH--CH₂ --, >C═CH--, >CH--O-- wherein only theunderscored atom participates in the ring system; and

r is 1, 2 or 3; and

Z is selected from ##STR3## wherein M₁, and M₂ independently are CH orN; and R⁵ is hydrogen, C₁₋₆ -alkyl, phenyl or benzyl; and

R³ is hydrogen, halogen, trifluoromethyl, nitro or cyano; and

R⁴ is hydrogen, halogen, trifluoromethyl, nitro, cyano, (CH₂)_(m) COR¹¹,(CH₂)_(m) OH or (CH₂)_(m) SO₂ R¹¹ wherein R¹¹ is hydroxy, C₁₋₆ -alkoxyor NHR¹², wherein R.sup.¹² is hydrogen or C₁₋₆ -alkyl; and m is 0, 1, or2; or

R⁴ is selected from ##STR4## or a pharmaceutically acceptable saltthereof.

The compounds of formula I may exist as geometric and optical isomersand all isomers, as separated, pure or partially purified stereoisomersor racemic mixtures thereof are included in the scope of the invention.Isomers may be separated by means of standard methods such aschromatographic techniques or fractional crystallisation of suitablesalts.

Preferably, the compounds of formula I exist as the individual geometricor optical isomers.

The compounds according to the invention may optionally exist aspharmaceutically acceptable acid addition salts or--when the carboxylicacid group is not esterified--as pharmaceutically acceptable metal saltsor--optionally alkylated--ammonium salts.

Examples of such salts include inorganic and organic acid addition saltssuch as hydrochloride, hydrobromide, sulphate, phosphate, acetate,fumarate, maleate, citrate, lactate, tartrate, oxalate or similarpharmaceutically acceptable inorganic or organic acid addition salts,and include the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) which are known to the skilledartisan.

Also included are the hydrates of the above mentioned acid additionsalts which the present compounds are able to form.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or by precipitation orcrystallisation.

The compounds of formula I may be administered in a pharmaceuticallyacceptable acid addition salt form or where possible as a metal or alower alkylammonium salt. Such salt forms exhibit approximately the sameorder of activity as the free base forms.

In the above structural formula and throughout the presentspecification, the following terms have the indicated meaning:

The term "C₁₋₆ -alkyl" as used herein, alone or in combination, refersto a straight or branched, saturated hydrocarbon chain having 1 to 6carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl,2,2-dimethylpropyl and 1,2,2-trimethylpropyl.

The term "C₁₋₆ -alkoxy" as used herein, alone or in combination, refersto a straight or branched monovalent substituent comprising a C₁₋₆-alkyl group linked through an ether oxygen having its free valence bondfrom the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy,ethoxy, propoxy, isopropoxy, butoxy, pentoxy.

The term "halogen" means fluorine, chlorine, bromine or iodine.

In a preferred embodiment of the invention R¹ and R² are selected fromhydrogen halogen, trifluoromethyl or C₁₋₆ -alkyl. Preferably R¹ and R²are hydrogen, halogen or methyl.

In a another preferred embodiment of the invention X is selected from--CH₂ CH₂ --, --CH═CH--, --O--CH₂ --, --CH₂ --O--, --OCH₂ O--, --S--CH₂-- or --CH₂ --S--. Preferably X is selected from --CH₂ CH₂ --, --OCH₂O--, --S--CH₂ -- or --CH₂ --S--.

In another preferred embodiment of the invention Y is selected from>N--CH₂ --, >C═CH-- or >CH--O-- wherein only the underscored atomparticipates in the ring system.

In another preferred embodiment of the invention r is 1 o r 2.

In another preferred embodiment of the invention Z is selected from##STR5## wherein M₁, and M₂ independently are CH or N.

In another preferred embodiment of the invention R³ is hydrogen,trifluoromethyl, nitro or cyano.

In another preferred embodiment of the invention R⁴ is hydrogen,trifluoromethyl, nitro, cyano or (CH₂)_(m) CO^(R) ¹¹.

In another preferred embodiment of the invention m is 0 or 1.

In yet another preferred embodiment of the invention R¹¹ is hydroxy.

Preferred compounds of the present invention include:

2-(4-(3-(12H-Dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)piperazin-1-yl)-3-pyridinecarboxylicacid,

2-(4-(3-(2,10-Dichloro-12H-dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-piperazin-1-yl)-3-pyridinecarboxylicacid,

2-(4-(3-(12H-Dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)piperazin-1-yl)-3-pyridinecarboxylicacid,

2-(4-(3-(2-Chloro-12H-dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)-piperazin-1-yl)-3-pyridinecarboxylicacid,

1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-4-(2-pyridyl)piperazine,

2-(4-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-propyl)-1-piperazinyl)-3-pyridine-carboxylicacid,

2-(4-(2-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-ethyl)-1-piperazinyl)-3-pyridinecarboxylicacid,

6-(4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl)-2-pyridinecarboxylicacid,

2-(4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylicacid,

2-(4-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl)-5-pyridinecarboxylicacid,

2-(4-(3-(3-Chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylicacid,

1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-4-(2-nitrophenyl)-piperazine,

2-(4-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-1-piperazinyl)benzonitrile,

2-(4-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-1-piperazinyl)-benzoicacid,

1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-4-(3-trifluoromethyl-2-pyridyl)piperazine,

2-(4-(2-(6,11-Dihydro-dibenzo[b,e]thiepin-11-ylidene)ethyl)piperazin-1-yl)-3-pyridinecarboxylicacid,

2-(4-(3-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylicacid,

2-(4-(2-(6,11-Dihydrodibenzo[b,e]thiepin-11-yloxy)ethyl)-1-piperazinyl)-3-pyridinecarboxylicacid,

6-(4-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)piperazin-1-yl)-2-pyridinecarboxylicacid,

2-(4-(3-(3-Methyl-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl-3-pyridinecarboxylicacid,

6-(4-(3-(Dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)-piperazin-1-yl)-pyridine-2-carboxylicacid,

or a pharmaceutically acceptable salt thereof.

It has been demonstrated that the novel compounds of formula I inhibitneurogenic inflammation which involves the release of neuropeptides fromperipheral and central endings of sensory C-fibres. Experimentally thiscan be demonstrated in animal models of histamine induced paw oedema(Europ. J. Pharmacol. 279, 227-231, 1995) in which the novel compoundsof formula I exhibit a potent inhibitory effect. Compounds of formula Imay be used to treat all painful, hyperalgesic and/or inflammatoryconditions in which C-fibres play a pathophysiological role by elicitingneurogenic pain or inflammation, i.e.:

Acutely painful conditions exemplified by migraine, postoperative pain,burns, bruises, post-herpetic pain (Zoster) and pain as it is generallyassociated with acute inflammation; chronic, painful and/or inflammatoryconditions exemplified by various types of neuropathy (diabetic,post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis,gout, inflammatory bowel disease, prostatitis, cancer pain, chronicheadache, coughing, asthma, itching, chronic pancreatitis, inflammatoryskin disease including psoriasis and autoimmune dermatoses, osteoporoticpain.

Further, it has been demonstrated that the compounds of general formulaI improve the glucose tolerance in diabetic ob/ob mice and that this mayresult from the reduced release of CGRP from peripheral nervous endings.Hence the compounds of general formula I may be used in the treatment ofNIDDM as well as ageing-associated obesity. Experimentally this has beendemonstrated by the subcutaneous administration of glucose into ob/obmice with or without previous oral treatment with a compound of generalformula I.

The compounds of formula I may be prepared by the following method:##STR6## A compound of formula II wherein R¹, R², X, Y and r are asdefined above and W is a suitable leaving group such as halogen,p-toluene sulphonate or mesylate may be reacted with an aza compound offormula III wherein Z is as defined above. This alkylation reaction maybe carried out in a solvent such as acetone, dibutylether, 2-butanone,methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or toluene inthe presence of a base e.g. sodium hydride and a catalyst, e.g. analkali metal iodide at a temperature up to reflux temperature for thesolvent used for e.g. 1 to 120 h. If esters have been prepared in whichR¹¹ is alkoxy, compounds of formula I wherein R¹¹ is OH may be preparedby hydrolysis of the ester group, preferably at room temperature in amixture of an aqueous alkali metal hydroxide solution and an alcoholsuch as methanol or ethanol, for example, for about 0.5 to 6 h.

Compounds of formula II and III may readily be prepared by methodsfamiliar to those skilled in the art.

Under certain circumstances it may be necessary to protect theintermediates used in the above methods e.g. a compound of formula IIIwith suitable protecting groups. The carboxylic acid group can, forexample, be esterified. Introduction and removal of such groups isdescribed in "Protective Groups in Organic Chemistry" J. F. W. McOrnieed. (New York, 1973).

PHARMACOLOGICAL METHODS

I. Histamine Induced Paw Oedema

The rat histamine paw oedema test was performed essentially as describedby Amann et al. (Europ. J. Pharmacol. 279, 227-231, 1995). In brief250-300 g male Sprague-Dawley rats were anaesthetized with pentobarbitalsodium, and placed on a 32 degree (Celsius) heated table. Ten minuteslater histamine (50 micoliter, 3 mg/ml) was injected in the right hindpaw and 20 minutes hereafter the paw swelling was determined by waterplethysmography (Ugo Basile). Test compounds were administeredintraperitoneally at 15 minutes before the anaesthetics.

II. Reduced Release of CGRP

ob/ob female mice, 16 weeks of age, where injected glucose (2 g/kg)subcutaneously. At times hereafter blood glucose was determined in tailvenous blood by the glucose oxidase method. At the end of the study theanimals were decapitated and trunk blood collected. Immunoreactive CGRPwas determined in plasma by radio-immuno-assay. Two groups of animalswere used. The one group was vehicle treated, whereas the other groupreceived a compound of formula I via drinking water (100 mg/l) for fivedays before the test.

Values for inhibition of histamine induced oedema response for somerepresentative compounds are recorded in table 1.

                  TABLE 1                                                         ______________________________________                                        Inhibition of histamin induced pain response at 1.0 mg/kg                            Example no.                                                                             % Oedema inhibition                                          ______________________________________                                        2            24                                                                 8 61                                                                        ______________________________________                                    

PHARMACEUTICAL COMPOSITIONS

The present invention also relates to pharmaceutical compositionscomprising a compound of formula I or a pharmaceutically acceptable saltthereof and, usually, such compositions also contain a pharmaceuticalcarrier or diluent. The compositions containing the compounds of thisinvention may be prepared by conventional techniques and appear inconventional forms, for example capsules, tablets, solutions orsuspensions.

The pharmaceutical carrier employed may be a conventional solid orliquid carrier. Examples of solid carriers are lactose, terra alba,sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate andstearic acid. Examples of liquid carriers are syrup, peanut oil, oliveoil and water.

Similarly, the carrier or diluent may include any time delay materialknown to the art, such as glyceryl monostearate or glyceryl distearate,alone or mixed with a wax.

The route of administration may be any route which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral, nasal, pulmonary or parenteral e.g. rectal, depot,transdermal, subcutaneous, intranasal, intramuscular, topical,intravenous, intraurethral, ophthalmic solution or an ointment, the oralroute being preferred.

If a solid carrier for oral administration is used, the preparation canbe tabletted, placed in a hard gelatine capsule in powder or pellet formor it can be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will usually be from about 25 mg to about 1g. If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatine capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

For nasal administration, the preparation may contain a compound offormula I dissolved or suspended in a liquid carrier, in particular anaqueous carrier, for aerosol application. The carrier may containadditives such as solubilising agents, e.g. propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabenes.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

A typical tablet which may be prepared by conventional tablettingtechniques contains

    ______________________________________                                        Core:                                                                           Active compound (as free compound 100 mg                                      or salt thereof)                                                              Colloidal silicon dioxide (Areosil ®) 1.5 mg                              Cellulose, microcryst. (Avicel ®)  70 mg                                  Modified cellulose gum (Ac-Di-Sol ®) 7.5 mg                               Magnesium stearate                                                            Coating:                                                                      HPMC approx.   9 mg                                                           *Mywacett ® 9-40 T approx. 0.9 mg                                       ______________________________________                                         *Acylated monoglyceride used as plasticizer for film coating.            

The compounds of the invention may be administered to a mammal,especially a human, in need of such treatment, prevention, elimination,alleviation, or amelioration of an indication related to all painful,hyperalgesic and/or inflammatory conditions in which C-fibres play apathophysiological role such as e.g. neurogenic pain, inflammation,migraine, neuropathy, itching and rheumatoid arthritis, as well asindications caused by or related to the secretion and circulation ofinsulin antagonising peptides, such as non-insulin-dependent diabetesmellitus (NIDDM) or ageing-associated obesity. Such mammals include alsoanimals, both domestic animals, e.g. household pets, and non-domesticanimals such as wildlife.

The compounds of the invention may be administered in the form of analkali metal or earth alkali metal salt thereof, concurrently,simultaneously, or together with a pharmaceutically acceptable carrieror diluent, especially and preferably in the form of a pharmaceuticalcomposition thereof, whether by oral, rectal, or parenteral (includingsubcutaneous) route, in an effective amount.

For the above indications the dosage will vary depending on the compoundof formula I employed, on the mode of administration and on the therapydesired. However, in general, satisfactory results are obtained with adosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mgto about 500 mg of compounds of formula I, conveniently given from 1 to5 times daily, optionally in sustained release form. Usually, dosageforms suitable for oral administration comprise from about 0.5 mg toabout 1000 mg, preferably from about 1 mg to about 500 mg of thecompounds of formula I admixed with a pharmaceutical carrier or diluent.

Suitable dosage ranges varies as indicated above depending as usual uponthe exact mode of administration, form in which administered, theindication towards which the administration is directed, the subjectinvolved and the body weight of the subject involved, and the preferenceand experience of the physician or veterinarian in charge.

Generally, the compounds of this invention are dispensed in unit dosageform comprising 50-200 mg of active ingredient in or together with apharmaceutically acceptable carrier per unit dosage.

Usually, dosage forms suitable for oral, nasal, pulmonal or transdermaladministration comprise from about 0.5 mg to about 1000 mg, preferablyfrom about 1 mg to about 500 mg of the compounds of formula I admixedwith a pharmaceutically acceptable carrier or diluent.

Any novel feature or combination of features described herein isconsidered essential to this invention.

EXAMPLES

The process for preparing compounds of formula I and preparationscontaining them is further illustrated in the following examples, which,however, are not to be construed as limiting.

Hereinafter, TLC is thin layer chromatography, CDCl₃ is deuterochloroform and DMSO-d₆ is hexadeutero dimethylsulfoxide. The structuresof the compounds are confirmed by either elemental analysis or NMR,where peaks assigned to characteristic protons in the title compoundsare presented where appropriate. ¹ H NMR shifts (δ_(H)) are given inparts per million (ppm). M.p. is melting point and is given in ° C. andis not corrected. Column chromatography was carried out using thetechnique described by W. C. Still et al, J. Org. Chem. (1978), 43,2923-2925 on Merck silica gel 60 (Art. 9385). Compounds used as startingmaterials are either known compounds or compounds which can readily beprepared by methods known per se.

Example 12-(4-(3-(12H-Dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)piperazin-1-yl)-3-pyridinecarboxylicacid hydrochloride ##STR7##

2,2'-Dihydroxybenzophenone (10.0 g, 46.7 mmol) and diiodomethane (13.1g, 49 mmol) was dissolved in dry N,N-dimethylformamide (180 ml). Driedfinely powdered potassium carbonate (9.2 g, 66.7 mmol) was added and themixture was heated at 105° C. for 16 h. After cooling to roomtemperature the reaction mixture was poured into ice water (500 ml). Theprecipitate was collected by filtration after 0.5 h, washed with wateron the filter and dissolved in a mixture of ethanol (80 ml) and 4 Nsodium hydroxide (20 ml). The solution was stirred at reflux temperaturefor 1 h, cooled and diluted with water (300 ml). The formed crystallineprecipitate was filtered off, washed with water (50 ml) and dried invacuo, affording 12H-dibenzo[d,g][1,3]dioxocin-12-one as a solid (9.5 g,90%).

M.p. 93-95° C.

A solution of cyclopropylmagnesium bromide in dry tetrahydrofuran(prepared from cyclopropylbromide (24.2 g, 0.2 mol), magnesium turnings(4.86 g, 0.2 mol) and dry tetrahydrofuran (70 ml) was placed under anatmosphere of nitrogen. A solution of the above ketone (9.05 g, 40 mmol)in dry tetrahydrofuran (50 ml) was added dropwise. The reaction mixturewas stirred at 40° C. for 1.5 h, cooled and added to an icecold mixtureof saturated ammonium chloride (400 ml) and ether (200 ml). The organiclayer was separated and the aqueous phase was extracted with ether (50ml). The combined organic extracts were washed with water (2×100 ml) andbrine (50 ml), dried (MgSO₄), evaporated in vacuo and stripped withtoluene (2×25 ml). This furnished 11.2 g12-cyclopropyl-12H-dibenzo[d,g][1,3]dioxocin-12-ol .

¹ H NMR (200 MHz, CDCl₃): δ 0.50 (d, 2H); 0.75 (d, 2H); 2.00 (m, 1H);5.14 (s, 2H); 6.9-7.4 (m, 6H); 7.81 (d, 2H).

To a solution of the above alcohol (6.21 g, 22 mmol) in drydichloromethane (225 ml) trimethylsilylbromosilane (3.71 g, 24.2 mmol)was added. The reaction mixture was stirred at room temperature for 1 hand poured on an icecold saturated sodium hydrogencarbonate solution (75ml). The organic phase was separated, washed with icewater (2×75 ml) andbrine (75 ml), dried (MgSO₄) and evaporated in vacuo. This afforded 7.95g crude 12-(3-bromo-1-propylidene)-12H-dibenzo[d,g][1,3]dioxocine, whichwas used in the next step without further purification.

A mixture of the above bromide (5.0 g, 15 mmol),2-(1-piperazinyl)-3-pyridinecarboxylic acid ethyl ester (3.54 g, 15mmol, prepared as described in J. Med. Chem. 31, 618-624 (1988)), sodiumiodide (2.23 g, 15 mmol) and potassium carbonate (5.1 g, 37 mmol) in2-butanone (70 ml) was heated at reflux temperature for 5 h. Aftercooling, the mixture was poured into diethyl ether (170 ml) and water(170 ml). The organic layer was separated, washed with water (2×100 ml),acidified with 2 N hydrochloric acid and washed with water (2×50 ml).The combined aqueous layers were made alkaline using a saturatedsolution of sodium hydrogen carbonate, and extracted withdichloromethane (200 ml). The organic extract was dried (MgSO₄) andevaporated in vacuo. The residue (4.35 g) was purified by chromatographyon silica gel using a mixture of benzene and ethyl acetate as eluent togive2-(4-(3-(12H-dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-piperazin-1-yl)-3-pyridinecarboxylicacid ethyl ester (3.71 g, 51%).

A mixture of the above ester (0.99 g, 2 mmol) and 20% sodium hydroxide(1.5 ml) in ethanol (13 ml) was stirred at room temperature for 4 h. Themixture was poured into dichloromethane (100 ml), acidified with 2 Nhydrochloric acid and washed with water (10 ml). The organic solutionwas dried (MgSO₄) and activated charcoal was added. The mixture wasstirred for 10 minutes, filtered and the solvent was removed in vacuo.The residue was triturated with acetone and the solid product wasoverlaid with ethyl acetate, stirred for 15 minutes, filtered off andwashed with ethyl acetate. After drying, the title compound (0.80 g,74%) was obtained.

M.p. 225-229° C. Calculated for C₂₇ H₂₇ N₃ O₄, HCl,0.25 C₄ H₈ O₂, 0.25C₂ H₅ OH: C, 64.89%; H, 6.02%; Cl, 6.72%; N, 7.96%; Found: C, 64.95%; H,5.86%; Cl, 6.73%; N, 7.94%.

Example 22-(4-(3-(2,10-Dichloro-12H-dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-piperazin-1-yl)-3-pyridinecarboxylicacid dihydrochloride ##STR8##

2,2'-Dihydroxy-5,5'-dichlorobenzophenone (12.1 g, 0.042 mol, prepared asdescribed in JACS 77, 543 (1955)) and diiodomethane (11.9 g, 0.044 mol)were dissolved in dry N,N-dimethylformamide (226 ml). Dried and powderedpotassium carbonate (8.3 g) was added and the mixture was heated at 105°C. for 5 h and left overnight at room temperature. The reaction mixturewas poured on ice (220 g). The precipitate was collected by filtrationand dissolved in diethyl ether (500 ml). The organic solution was washedwith 5% sodium hydroxide (50 ml), dried (MgSO₄) and evaporated in vacuo.This afforded 12 g (96%) of2,10-dichloro-12H-dibenzo[d,g][1,3]dioxocin-12-one as a solid.

To a solution of cyclopropylmagnesium bromide in dry tetrahydrofuran(prepared from cyclopropylbromide (15.7 g, 0.130 mol), magnesiumturnings (3.15 g, 0.130 mol) and dry tetrahydrofuran (45 ml)), asolution of the above ketone (7.65 g, 0.026 mol) in dry tetrahydrofuran(30 ml) was added over 5 minutes under cooling. The reaction mixture wasstirred at 38-42° C. for 3 h, cooled in an ice-bath, and a mixture ofsaturated ammonium chloride (260 ml) and diethyl ether (130 ml) wasadded. The reaction mixture was then filtered, and the organic layer wasseparated and the aqueous phase was extracted with diethyl ether (35ml). The combined organic extracts were washed with water (2×70 ml) andbrine (70 ml), dried (MgSO₄) and evaporated in vacuo. The crude productwas purified by column chromatography on silica gel (140 g) usingbenzene as eluent. This afforded 8.75 g (98%) of2,10-dichloro-12-cyclopropyl-12H-dibenzo[d,g][1,3]dioxocin-12-ol as asolid.

To a solution of the above alcohol (8.75 g, 0.027 mol) in drydichloromethane (245 ml) trimethylsilyl bromide (4.02 g, 0.026 mol) wasadded. The reaction mixture was stirred at room temperature for 1 h andpoured on an ice cold saturated sodium hydrogencarbonate solution (80ml). The organic phase was separated, washed with water (2×80 ml) andbrine (80 ml), dried (MgSO₄) and evaporated in vacuo. This afforded 9.12g of an oil, which was purified by column chromatography on silica gel(250 g) using a mixture of cyclohexane and benzene (3:1) as eluent. Thisyielded 6.61 g (62%) of2,10-dichloro-12-(3-bromo-1-propylidene)-12H-dibenzo[d,g][1,3]dioxocineas an oil which crystallized on standing.

A mixture of the above bromide (3 g, 0.008 mol),2-(1-piperazinyl)-3-pyridinecarboxylic acid ethyl ester (1.76 g, 0.0075mol), potassium carbonate (3.1 g, 0.022 mol) and sodium iodide (1.1 g,7.3 mmol) in 2-butanone (35 ml) was heated at reflux temperature for 6h. After cooling to room temperature, the reaction mixture was dilutedwith acetone, filtered and evaporated in vacuo. The solid residue waspurified by column chromatography on silica gel (100 g) using chloroformas eluent. This afforded 2.7 g (65%) of2-(4-(3-(2,10-dichloro-12H-dibenzo[d,g][1,3]dioxocin-12-ylidene)-1-propyl)-piperazin-1-yl)-3-pyridinecarboxylicacid ethyl ester as an oil.

The above ester (2.7 g, 4.87 mmol) was dissolved in ethanol (30 ml) anda solution of sodium hydroxide (0.74 g) in water (2.8 ml) was added. Themixture was stirred at room temperature for 48 h. Concentratedhydrochloric acid (2.8 ml) was added followed by dichloromethane (100ml). The organic layer was separated, dried (MgSO₄) and evaporated invacuo. The resulting foam was stirred with hot acetone (1 50 ml), theproduct was filtered off and washed with acetone, affording 1.8 g (62%)of the title compound.

¹ H NMR (250 MHz, DMSO-d₆): δ_(H) : 8.31 (dd, J=1.9 Hz and 4.7 Hz, 1 H);8.04 (dd, J=1.9 Hz and 7.5 Hz, 1 H); 7.53 (d, J=2,5 Hz, 1 H); 7.32 (dd,J=2.5 Hz and 8.5 Hz, 1 H); 7.25 (dd, J=2.5 Hz and 8.5 Hz, 1 H); 7.21 (d,J=2.5 Hz, 1 H); 7.10 (d, J=8.5 Hz, 1 H); 6.97 (d, J=8.5 Hz); 6.95 (dd,J=4.7 Hz and 7.5 Hz), S 2 H; 6.15 (t, J=7.5 Hz, 1 H); 5.86 (s, 2 H);3.73(bs, 4 H); 3.25 (bt, 6 H); 2.50 (q, J=7.5 Hz, 2 H). Calculated for C₂₇H₂₅ Cl₂ N₃ O₄, 2 HCl, 0.5 H₂ O: C, 53.30%; H, 4.64%; N, 6.91%; Cl,23.31%; Found: C, 53.41%; H, 4.60%; N, 6.73%; Cl, 22.71%.

Example 32-(4-(3-(12H-Dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)piperazin-1-yl)-3-pyridinecarboxylicacid dihydrochloride ##STR9##

N-(2-Hydroxyphenyl)formamide (16.0 g, 130 mmol) was dissolved in 99.9%ethanol (65 ml). Sodium methoxide (7.0 g, 130 mmol) was suspended in99.9% ethanol (70 ml) and added dropwise over 30 minutes. The resultingmixture was stirred for 30 minutes. 1-Bromo-2-chloromethoxybenzene (26.1g, 118 mmol, synthesis described in J. Heterocycl. Chem., 11, 1974,331-337) was added dropwise over 15 minutes. The reaction mixture wasstirred for 2.5 h at room temperature, heated at reflux temperature for2 h, and stirred at room temperature overnight. The mixture was filteredand the filtrate evaporated. The residue was dissolved in toluene (500ml) and washed with a saturated sodium carbonate solution (2×200 ml).The organic phase was dried (MgSO₄) and evaporated. The residue wassuspended in ethanol (40 ml), filtered and washed with ethanol (3×10ml). After drying, N-(2-(2-bromophenoxymethoxy)phenyl)formamide (14.1 g,37%) was obtained.

The above formamide (6.8 g, 21 mmol) was suspended in Dowtherm (75 ml),and potassium carbonate (3.9 g, 28 mmol) was added, followed by copper(1.1 g, 17 mmol) and copper bromide (1.5 g, 11 mmol). The reactionmixture was heated at 180° C. overnight. After cooling, the mixture wasfiltered, and the filtercake was washed with dichloromethane. Dowthermand solvent was distilled off, and ethanol (200 ml) was added to theresidue, which was left overnight. 4 M Sodium hydroxide (14 ml) wasadded and the mixture was heated at reflux temperature for 1 h. Aftercooling, the mixture was filtered and evaporated. The residue wassuspended in ethyl acetate (200 ml) and water (100 ml). The phases wereseparated and the organic phase was washed with water (2×75 ml). Theaqueous phases were extracted with ethyl acetate (100 ml) and thecombined organic extracts were evaporated. The residue was suspended inwarm cyclohexane (100 ml), and left cooling under stirring. Theprecipitated solid was filtered off and dried, affording12H-dibenzo[d,g][1,3,6]dioxazocine (4.57 g, 50%).

The above dioxazocine (4.0 g, 19 mmol) was dissolved in dryN,N-dimethylformamide (150 ml). Sodium hydride (1.13 g, 28 mmol, 60%dispersion in oil) was added in portions, and the resulting mixture wasstirred for 30 minutes at room temperature. 1-Bromo-3-chloropropane (4.6ml, 47 mmol) was slowly added dropwise, and the reaction mixture wasstirred at room temperature overnight. More sodium hydride (0.56 g, 14mmol) was added, and stirring was continued for 6 h. More sodium hydride(0.56 g, 14 mmol) was added, and stirring was continued overnight.Ammonium chloride (3.2 g) was added, and the mixture was stirred for 30minutes. Water was added (300 ml), and the mixture was extracted withdichloromethane (2×250 ml). The combined organic extracts were dried(MgSO₄) and evaporated. The residue was purified by columnchromatography on silica gel using a mixture of heptane and ethylacetate (6:1) as eluent. This afforded12-(3-chloropropyl)-12H-dibenzo[d,g][1,3,6]dioxazocine (2.18 g, 40%).

The above chloride (1.35 g, 4.66 mmol) and potassium iodide (5.0 g, 30mmol) in methyl ethyl ketone (150 ml) was heated at reflux temperaturefor 4.5 h. 2-(1-Piperazinyl)-3-pyridinecarboxylic acid ethyl ester (3.0g, 12 mmol) was added followed by potassium carbonate (2.25 g, 16.3mmol). The reaction mixture was heated at reflux temperature for 19 h.After cooling, the mixture was filtered, the filtercake was washed withmethyl ethyl ketone, and the filtrate was evaporated. The residual oilwas purified by column chromatography on silica gel (800 ml) using amixture of heptane and ethyl acetate (1:3) as eluent. This afforded2-(4-(3-(12H-dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)piperazin-1-yl)-3-pyridinecarboxylicacid ethyl ester (0.71 g, 32%) as an oil.

The above ester (0.50 g, 1.22 mmol), dissolved in a solution of sodiumhydroxide (0.24 g, 6 mmol) in ethanol (30 ml) and water (3 ml) wasstirred at room temperature for 25 h. The pH of the mixture was adjustedto 3 by addition of 1 N hydrochloric acid (6 ml). The mixture wasextracted with dichloromethane (2×40 ml), the combined organic phaseswere washed with brine (50 ml), dried (MgSO₄) and the solvent wasremoved in vacuo. The residue was triturated with isopropyl acetate (15ml) and the solid product was filtered off. Part of the product (275 mg)was suspended in acetone (160 ml), evaporated in vacuo and dried,affording the title compound (0.23 g, 75%).

Calculated for C₂₆ H₂₈ N₄ O₄, 2 HCl; 0.5 H₂ O, 0.5 C₅ H₁₀ O₂ C, 57.67%;H, 6.07%; N, 9.44%; Found: C, 57.78%; H, 6.02%; N, 9.42%.

HPLC retention time=18.42 minutes (5 μm C184×250 mm column, eluting witha 20-80% gradient of 0.1% trifluoriacetic acid/acetonitrile and 0.1%trifluoroacetic acid/water over 30 minutes at 30° C.

Example 42-(4-(3-(2-Chloro-12H-dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)-piperazin-1-yl)-3-pyridinecarboxylicacid dihydrochloride ##STR10##

A suspension of 2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine (10.65 g, 43mmol, described in J.Mol.Struct., 131, 1985, 131-140) and3-chloropropionyl chloride (6.55 g, 51.6 mmol) in dry toluene (100 ml)was heated at reflux temperature for 5 h. After cooling to roomtemperature, the reaction mixture was washed with a saturated solutionof sodium bicarbonate (50 ml). The organic layer was dried (MgSO₄), andevaporated in vacuo, affording2-chloro-12-(3-chloropropionyl)-12H-dibenzo[d,g][1,3,6]dioxazocine(12.85 g , 88%).

To a cooled suspension of lithium aluminium hydride (3.0 g, 79 mmol) indry tetrahydrofuran (80 ml), concentrated sulfuric acid (3.87 g, 39.5mmol) was added dropwise at a rate to maintain a temperature <12° C. Themixture was stirred at room temperature for 1.5 h. A solution of theabove amide (12.8 g, 37.8 mmol) in dry tetrahydrofuran (80 ml) was addeddropwise and stirring was continued for 2 h. The reaction was quenchedby careful addition of ethyl acetate (100 ml) followed by water (5.7ml). Filtration of the mixture and evaporation of the filtrate in vacuoafforded 2-chloro-12-(3-chloropropyl)-12H-dibenzo[d,g][1,3,6]dioxazocineas a foam.

A mixture of the above crude chloride (1.14 g, 3.5 mmol),2-(1-piperazinyl)-3-pyridinecarboxylic acid methyl ester (0.78 g, 3.5mmol), dry potassium carbonate (1.45 g, 10.5 mmol), sodium iodide (0.53g, 3.5 mmol) and 2-butanone (15 ml) was heated at reflux temperature for48 h. The reaction mixture was evaporated in vacuo. The remainder wasdissolved in toluene (25 ml), washed with water (2×25 ml) and evaporatedin vacuo. The crude product (1.15 g) was purified by columnchromatography on silica gel using a mixture of ethyl acetate andtoluene (1:1) containing triethylamine (2.5%) as eluent. This afforded2-(4-(3-(2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylicacid methyl ester (1.10 g, 62%) as an oil.

The above ester (1.10 g, 2.16 mmol) was dissolved in ethanol (10 ml) and2 N sodium hydroxide (3.57 ml, 7.13 mmol) was added. The mixture wasstirred at room temperature for 16 h. The ethanol was evaporated invacuo and the remainder was diluted with water (25 ml). pH was adjustedto 6 by addition of 6 N hydrochloric acid and the aqueous solution wasextracted with dichloromethane (3×15 ml). The combined organic extractswere dried (MgSO₄) and evaporated in vacuo. The remainder was dissolvedin tetrahydrofuran (25 ml) and a 2.5 N solution of hydrogen chloride inether (1.67 ml, 4.18 mmol) was added dropwise. The mixture was stirredfor 3 h, and the precipitate filtered off and dried to afford 0.86 g(75%) of the title compound.

M.p. 165-173° C. Calculated for C₂₆ H₂₇ CIN₄ O₄, 2 HCl: C, 54.99%; H,5.15%; N, 9.87%; Found: C, 54.8%; H, 5.2%; N, 9.65%.

Example 51-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-4-(2-pyridyl)piperazinedihydrochloride ##STR11##

A mixture of5-(3-bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene(3.13 g, 10 mmol, prepared as described in WO 9518793),1-(2-pyridyl)piperazine (2.5 g, 15 mmol, prepared similarly as describedin J.Org,Chem. 1953, 18, 1484), potassium carbonate (2.8 g, 20 mmol) andN,N-dimethylformamide (40 ml) was stirred at room temperature for 16 h,and at 50-55° C. for 8 h. After cooling, the mixture was diluted withbenzene (150 ml) and washed with water (3×100 ml). The organic layer wasextracted with 3 N hydrochloric acid (100 ml). The acidic aqueous layerwas made alkaline with 5 N sodium hydroxide (60 ml) to pH 12 andextracted with benzene (100 ml). The benzene solution was dried (K₂ CO₃)and filtered over silica gel (12 g). Evaporation in vacuo provided anoil (2.98 g, 75%). This was dissolved in ethanol (20 ml), acidified withhydrogen chloride in diethyl ether (3 mmol/ml, 8 ml) and precipitatedwith diethyl ether (20 ml). The precipitate was filtered off, washedwith diethyl ether and dried to give 2.1 g (44%) of the title compound.

M.p. 152-155° C. Calculated for C₂₇ H₂₉ N₃, 2 HCl , H₂ O: C, 66.66%; H,6.84%;N, 8.64%; Cl, 14.58%; Found: C, 67.27%; H, 6.52%;N, 8.76%; Cl14.19%:

Example 62-(4-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-1-piperazinyl)-3-pyridine-carboxylicacid hydrochloride ##STR12##

A mixture of 2-(1-piperazinyl)-3-pyridinecarboxylic acid ethyl ester(4.6 g, 0.019 mol),3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propylmethanesulfonate (5.0 g, 0.015 mol) and potassium carbonate (4.8 g) inN,N-dimethylformamide (50 ml) was heated to 60° C. for 5 h. Afterstanding overnight, the solid was filtered off and washed with benzene.The filtrate was diluted with benzene (200 ml) and washed with water(4×100 ml). The organic solution was dried (MgSO₄) and the solventevaporated in vacuo. The residue (7.8 g) was purified by columnchromatography on silica gel using benzene and a benzene-ethyl acetatemixture as eluents, affording2-(4-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylicacid ethyl ester (3.4 g, 48%) as an oil.

A mixture of the above ester (2.1 g, 4.5 mmol) and 20% sodium hydroxide(3.0 ml) in ethanol (21 ml) was stirred at room temperature for 16 h.The solution was poured into dichloromethane (250 ml) and acidified with2 N hydrochloric acid. The organic phase was washed with water (10 ml),dried (MgSO₄) and the solvent evaporated in vacuo. The foamy residue wasstripped with acetone and crystallized from acetone, affording 1.5 g(70%) of the title compound.

M.p. 224-230° C. Calculated for C₂₈ H₂₉ N₃ O₂, HCl, 0.25 H₂ O, 0.5 C₃H6O: C, 69.53%; H, 6.63%; Cl, 6.96%; N, 8.25%; Found: C, 69.76%; H,6.76%; Cl, 7.00%; N, 8.17%

Example 7 2-(4-(2-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-l-ethyl)-1-piperazinyl)-3-pyridinecarboxylic acid hydrochloride ##STR13##

5-(2-Hydroxyethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (2.5 g, 0.0104mol, prepared similarly as described in Fr. Pat. 1,215 599) andtriethylamine (2.8 g, 0.028 mol) was dissolved in benzene (90 ml). Asolution of methanesulfonyl chloride (1.66 g, 0.0145 mol) in benzene (10ml) was added dropwise at 15-20° C. for 10 minutes under cooling on acold water bath. When addition was complete the reaction mixture wasstirred 1 h at room temperature. Water (35 ml) was added, the organiclayer was separated, washed with water (25 ml), dried (MgSO₄), andevaporated in vacuo. The methanesulfonate (3.2 g, 97%) was dissolved inacetone (55 ml) and 2-(1-piperazinyl)-3-pyridinecarboxylic acid ethylester (2.64 g, 0.0112 mol) and potassium carbonate (4.0 g) were added.The reaction mixture was heated at 50-55° C. for 28 h. The mixture wasfiltered and the solvent was removed by evaporation in vacuo. The cruderesidue (5.7 g) was purified by column chromatography on silica gel (65g) using a mixture of benzene and chloroform as eluent. This afforded2.0 g (43%) of2-(4-(2-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-ethyl)-1-piperazinyl)-3-pyridinecarboxylicacid ethyl ester as an oil.

The above ester was dissolved in ethanol (5 ml) and 4 N sodium hydroxide(5 ml) was added. The mixture was stirred at room temperature for 16 h.Dichloromethane (200 ml) was added followed by concentrated hydrochloricacid (3 ml). The solid was filtered off, washed with acetone, stirredwith water (2×25 ml), filtered and washed with acetone. The crudeproduct was dissolved in warm N,N-dimethylformamide, benzene was addedand the mixture was cooled overnight. The precipitate was filtered off,washed with benzene and dried, affording 0.9 g (44%) of the titlecompound.

M.p. 240-245° C. Calculated for C₂₆ H₂₈ N₄ O₂ , HCl, 0.5 H₂ O: C,65.87%; H, 6.38%; N, 11.82%; Cl, 7.48%; Found: C, 65.82%; H, 6.23%; N,11.66%; Cl, 7.90%.

Example 86-(4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl)-2-pyridinecarboxylicacid hydrochloride ##STR14##

To a suspension of 6-chloropyridine-2-carboxylic acid (8.3 g, 0.0525mol, prepared as described in Chem.Ber.45, 2456 (1912)) in dioxane (25ml), thionyl chloride (9.4 ml, 0.13 mol) was added and the resultingmixture was stirred at 70° C. for 4 h. The reaction mixture wasconcentrated in vacuo and a mixture of dioxane (8.3 ml) and ethanol(16.6 ml) was added. The reaction mixture was heated to 70° C. for 2 h,triethylamine (8.3 ml), ethanol (4.1 ml) and water (8.3 ml) were addedand the reaction mixture was again concentrated. The residue wasdistributed between diethyl ether (28 ml) and water (18 ml) and thephases were separated. The aqueous layer was extracted with diethylether (30 ml) and the combined organic layers were dried (MgSO₄) andevaporated in vacuo. This afforded 8.82 g (91%) of6-chloropyridine-2-carboxylic acid ethyl ester as an oil.

A mixture of the above ester (8.6 g, 0.046 mol), anhydrous piperazine(41 g, 0.476 mol) and sodium iodide (0.46 g) in toluene (145 ml) wereheated at reflux temperature for 2.5 h. After cooling to about 80° C.,piperazine was filtered off and the filtrate was mixed with water (250ml) and diethyl ether (100 ml). The organic layer was separated andwashed with water (2×50 ml) and brine (50 ml), dried (MgSO₄) andevaporated, affording 4.6 g of an oil. The aqueous layer was extractedwith chloroform (5×50 ml), the combined organic phases were washed withwater and brine as above, dried and evaporated, affording an additional3.2 g of an oil. Both crops were purified by column chromatography onsilica gel (200 g) using a mixture of chloroform and ethanol (9:1) aseluent. This afforded 5 g (46%) of6-(1-piperazinyl)-2-pyridinecarboxylic acid ethyl ester as an oil.

A mixture of the above ester (2.20 g, 9.35 mmol),(10,11-dihydro-5H-dibenzo[b,f]l-azepin-5-yl)-1-propyl)methane sulfonate(2.82 g, 8.51 mmol) and potassium carbonate (3.3 g, 0.0239 mol) inacetone (47 ml) was heated at reflux temperature for 16 h. The reactionmixture was filtered and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel (100 g) using chloroform aseluent. This afforded 1.21 g (30%) of6-(4-(3-(10,11-dihydro-5H-dibenzo[b,f]-azepin-5-yl)-1-propyl)-1-piperazinyl)-2-pyridinecarboxylicacid ethyl ester as an oil.

A mixture of the above ester (1.06 g, 2.25 mmol), ethanol (10 ml), asolution of sodium hydroxide (0.342 g) and water (1.3 ml) was stirred atroom temperature for 48 h. Concentrated hydrochloric acid (1.25 ml) wasadded followed by dichloromethane (60 ml). The phases were separated,and the organic phase was dried (MgSO₄) and evaporated in vacuo. Theresidue was re-evaporated with acetone (30 ml) and stirred with hotethanol (30 ml). This afforded after drying, 0.45 g (42%) of the titlecompound.

Calculated for C₂₇ H₃₀ N₄ O₂, HCl: C, 67.70%; H, 6.52%; N, 11.70%; Cl,7.40%; Found: C, 67.26%; H, 6.70%; N, 11.63%; Cl, 7.31%.

Example 92-(4-(3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylicacid dihydrochloride ##STR15##

A mixture of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine(4.54 g, 16.7 mmol), 2-piperazinyinicotinic acid methyl ester 3.7 g,16.7 mmol), dry potassium carbonate (6.92 g, 50.1 mmol), sodium iodide(2.5 g, 16.7 mmol) and 2-butanone (50 ml) was heated at refluxtemperature for 60 h. After cooling to room temperature, toluene (100ml) and water (100 ml) were added. The organic layer was separated,washed with water (2×50 ml) and evaporated in vacuo. The crude productwas purified by column chromatography on silica gel using a mixture oftoluene and ethyl acetate (3:1) containing triethylamine (2.5%) aseluent. This afforded 2.3 g (30%) of2-(4-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylicacid methyl ester as an oil.

A mixture of the above ester (2.3 g, 5.04 mmol) dissolved in a mixtureof 2 N sodium hydroxide (8.32 ml, 16.63 mmol) and ethanol (25 ml) wasstirred at room temperature for 16 h. The ethanol was evaporated invacuo. and the remainder was diluted with water (50 ml). 2 NHydrochloric acid (20 ml) was added, and the solution was washed withdiethyl ether (25 ml). The aqueous phase was extracted withdichloromethane (3×30 ml). The combined organic extracts were dried(MgSO₄) and evaporated in vacuo to afford a foam. This was crystallizedfrom tetrahydrofuran, filtered and dried, affording 1.20 g (50%) of thetitle compound.

M.p. 168-171° C. Calculated for C₂₇ H₃₀ N₄ O₂, 1.75 HCl: C,64.04%;H,6.32%; N,11.06%; Cl,12.25%; Found: C,63.72%; H,6.42%; N,10.68%;Cl,11.99%.

Example 102-(4-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl)-5-pyridinecarboxilicacid hydrochloride ##STR16##

A mixture of 2-bromopyridine-5-carboxylic acid methyl ester (1.40 g, 6.5mmol) and piperazine (5.59 g, 65 mmol) was dissolved in acetonitrile (50ml) and heated at reflux temperature for 2.5 h. The reaction mixture wasconcentrated in vacuo, dissolved in dichloromethane (50 ml) andextracted with water (3×50 ml). The organic solution was dried (MgSO₄)and evaporated in vacuo, affording 0.80 g (56%) of2-(1-piperazinyl)-5-pyridinecarboxylic acid methyl ester.

M.p. 91-92° C.

A mixture of the above ester (0.73 g, 3.3 mmol),5-(3-chloropropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (0.9 g, 3.3mmol), dry potassium carbonate (1.37 g, 9.9 mmol), sodium iodide (0.5 g,3.3 mmol) and 2-butanone (10 ml) was heated at reflux temperature for 24h. After cooling to room temperature, dichloromethane (25 ml) and water(25 ml) were added to the reaction mixture. The organic layer wasseparated, washed with water (2×10 ml) and evaporated in vacuo. Thecrude residue was purified by column chromatography on silica gel usinga mixture of toluene and ethyl acetate (1:1) containing triethylamine(2.5%) as eluent. This afforded 0.65 g (43%) of2-(4-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl)-5-pyridinecarboxylicacid methyl ester as an oil.

The above ester (0.65 g, 1.25 mmol), dissolved in a mixture of 2 Nsodium hydroxide (2.06 ml, 4.13 mmol) and ethanol (10 ml) was stirred atroom temperature for 16 h. The ethanol was evaporated in vacuo and theremainder was diluted with water (30 ml). 2 N Hydrochloric acid (20 ml)was added and the solution was washed with diethyl ether (25 ml). Theaqueous phase was extracted with dichloromethane (3×15 ml). The combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo to 20 ml.The precipitate was filtered off and dried to afford 0.33 g (60%) of thetitle compound.

M.p. 240-244° C. Calculated for C₂₇ H₃₀ N₄ O₂, HCl, 0.5 H₂ O: C,66.45%;H,6.61%; N,11.48%; Cl,7.26%; Found: C,66.39%; H,6.64%; N,11.22%;Cl,7.08%.

Example 112-(4-(3-(3-Chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylicacid dihydrochloride ##STR17##

To a solution of 3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepine (5.0 g,22 mmol) in toluene (20 ml), 3-chloropropionyl chloride (3.32 g, 26mmol) in toluene (8 ml) was added dropwise. The reaction mixture wasstirred at 95° C. for 2 h and left stirring at room temperatureovernight. 2 N Sodium hydroxide (25 ml) followed by toluene (50 ml) wereadded, and the phases were separated. The toluene phase was washed with2 N sodium hydroxide (2×25 ml), water (3×30 ml) and brine (30 ml). Theorganic phase was dried (MgSO₄) and evaporated in vacuo. The residue wasstripped with methanol (30 ml) and the residue was suspended in ethylacetate (8 ml), stirred and filtered off. The solid was washed withethyl acetate (10 ml) and dried. This afforded 4.0 g (57%) of3-chloro-1-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propan-1-one

A 1.0 M solution of lithium aluminium hydride in tetrahydrofuran (26.2ml, 26 mmol) was introduced into a 250 ml dry three-necked flask undernitrogen. Under cooling (ice bath), concentrated sulphuric acid (0.7 ml)was slowly added dropwise. The mixture was stirred for 15 minutes on anice bath and subsequently 45 minutes at room temperature. The aboveamide (4.2 g, 13 mmol) was dissolved in tetrahydrofuran (40 ml) andslowly added dropwise. The reaction mixture was left stirring for 1.5 h.Water (1 ml) was added dropwise, followed by 4 N sodium hydroxide (1 ml)and subsequently water (3 ml). The mixture was left stirring for 30minutes, filtered (hyflo) and evaporated. The residue was dissolved inethyl acetate (50 ml), dried (MgSO₄) and evaporated to give 3.5 g (88%)of 3-chloro-5-(3-chloropropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine.

Potassium iodide (2.8 g, 17 mmol) and methyl ethyl ketone (70 ml) washeated at 80° C. for 1 h. The above chloride (0.8 g, 3 mmol) wasdissolved in methyl ethyl ketone (10 ml) and added. The mixture washeated at reflux temperature for 50 minutes. Potassium carbonate (1.25g, 9 mmol) was added followed by 2-(1-piperazinyl)-3-pyridine carboxylicacid methyl ester (1.0 g, 4 mmol) in methyl ethyl ketone (10 ml). Thereaction mixture was stirred at 78° C. overnight. After cooling, themixture was filtered (hyflo) and evaporated. The residue was purified bycolumn chromatography on silica gel using a mixture of heptane and ethylacetate (1:1) as eluent. This afforded 0.33 g (26%) of2-(4-(3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl-3-pyridinecarboxylic acid ethyl ester.

TLC: R_(f) =0.17 (SiO₂ : ethyl acetate/heptane=1:1).

The above ethyl ester (0.33 g, 0.67 mmol) was dissolved in ethanol (8ml). 4 N Sodium hydroxide (0.34 ml) was added, and the reaction mixturewas stirred for 2 h at room temperature, and left in a freezerovernight. Stirring at room temperature was continued for 24 h. More 4 Nsodium hydroxide (0.34 ml) was added, stirring was continued for 2 h,additional 4 N sodium hydroxide was added (0.34 ml) and stirring wascontinued for 3.5 h. 4 N Hydrochloric acid (1.18 ml) was added, followedby water (20 ml) and dichloromethane (100 ml). The phases wereseparated, and the organic phase was dried (MgSO₄) and evaporated. Theresidue was stripped with acetone (2×30 ml), stirred with isopropylacetate (3-5 ml) for 5 minutes, filtered off and dried. Yield 0.18 g(51%) of the title compound as an amorphous powder.

Calculated for C₂₇ H₂₉ CIN₄ O₂, 2HCl, 0.25 C₅ H₉ O₂ : C, 62.98%; H,6.03%; N, 10.40%; Found: C, 63.31%; H, 6.36%; N, 10.16%

HPLC retention time=23.82 minutes (5 μm C184×250 mm column, eluting witha 20-80%; gradient of 0.1% trifluoriacetic acid/acetonitrile and 0.1%trifluoroacetic acid/water over 30 minutes at 30° C .

Example 121-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-4-(2-nitrophenyl)-piperazinehydrochloride ##STR18##

2-Fluoronitrobenzene (11.4 g, 81 mmol) was dissolved indimethylsulfoxide (200 ml), and piperazine (56.4 g, 0.65 mol) and sodiumcarbonate (20.6 g, 0.2 mol) were added. The mixture was stirred at 130°C. for 16 h. After cooling, toluene (300 ml) was added and the mixturewas washed with water (3×300 ml) and 1 N sodium hydroxide (300 ml). Theorganic phase was dried (MgSO₄) and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel, eluting first with amixture of ethyl acetate, heptane and triethyl amine (5:5:0.25), thenwith a mixture of ethyl acetate and triethyl amine (9:1), and finallywith a mixture of methanol and triethyl amine (40:1). This afforded1-(2-nitrophenyl)-piperazine (8.08 g, 48%).

TLC: R_(f) =0.27 (SiO₂ : ethyl acetate/methanol/triethylamine=1:1:0.025)

The above piperazine (1.51 g, 7.3 mmol) was dissolved in methyl ethylketone (50 ml), and5-(3-bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene(2.28 g, 7.3 mmol), potassium iodide (0.96 g, 15 mmol) and potassiumcarbonate (6.0 g, 44 mmol) were added, and the resulting mixture wasstirred at reflux temperature for 24 h. After cooling, ethyl acetate(100 ml) was added and the mixture was washed with water (2×100 ml),dried (MgSO₄) and concentrated in vacuo. The residue was purified byflash chromatography on silica gel using a mixture of ethyl acetate andheptane (1:2) as eluent, to give 2.18 g (68%) of the free base. This wasdissolved in diethyl ether (30 ml) and 1 N hydrochloric acid in diethylether (5 ml) was added. The precipitated solid was isolated byfiltration and dried in vacuo to give 1.83 g (53%) of the title compoundas a solid.

M.p. 204-206° C. Calculated for C₂₈ H₂₉ N₃ O₂, HCl: C, 70.65%; H, 6.35%;N, 8.83%; Found: C, 70.50%; H, 6.51%; N, 8.61%.

Example 132-(4-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-1-piperazinyl)benzonitrile##STR19##

Piperazine (6.0 g, 69 mmol) was dissolved in dimethylsulfoxide (50 ml),2-fluorobenzonitrile (0.95 ml, 9 mmol) and potassium carbonate (2.2 g,17 mmol) were added and the mixture was stirred at room temperature for16 h. Water (100 ml) was added and the mixture was extracted withtoluene (2×100 ml). The combined organic extracts were washed with 1 Nsodium hydroxide (3×75 ml), dried (MgSO₄) and concentrated in vacuo togive 1.48 g (88%) 2-(1-piperazinyl)benzonitrile as an oil.

TLC: R_(f) =0.12 (SiO₂ : ethyl acetate/triethyl amine=4:1).

The above benzonitrile (4.89 g, 26 mmol) was dissolved in methyl ethylketone (100 ml), and potassium carbonate (21.7 g, 157 mmol), potassiumiodide (3.45 g, 52 mmol), and5-(3-bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene(8.18 g, 26 mmol), were added. The resulting mixture was stirred atreflux temperature for 18 h. After cooling to room temperature, ethylacetate (200 ml) was added and the mixture was washed with water (2×150ml), dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby flash chromatography on silica gel eluting first with a mixture ofethyl acetate and heptane (1:4), and then with a mixture of ethylacetate and heptane (1:2). This afforded 5.60 g of the title compound asa solid.

M.p. 112-114° C. Calculated for C₂₉ H₂₉ N₃ : C, 83.02%; H, 6.97%; N,10.02%; Found: C, 83.25%; H, 7.14%; N, 9.93%.

Example 142-(4-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-1-piperazinyl)-benzoicacid hydrochloride ##STR20##

2-(4-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-1-piperazin)-benzonitrile(0.30 g, 0.72 mmol, prepared as described in example 13) was added to amixture of water (0.6 ml), sulphuric acid (0.6 ml), and acetic acid (0.6ml). The resulting mixture was heated at reflux temperature for 24 h andstirred at room temperature for 3 days. 1 N Sodium hydroxide (20 ml) wasadded and the mixture was washed with diethyl ether (3×20 ml). Theaqueous phase was acidified with 5 N hydrochloric acid to pH 1. Themixture was extracted with dichloromethane (2×50 ml), the combinedextracts were dried (MgSO₄) and evaporated in vacuo to give 0.21 g (56%)of the title compound as an amorphous solid.

Calculated for C₂₉ H₂₃ N₂ O₂, HCl, 1.5 H₂ O: C, 69.38%; H, 6.83%; N,5.58%; Found: C, 69.69%; H, 6.69%; N, 5.06%. El-MS (70 eV): m/e=438 (M⁺,0.1%)

Example 151-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-4-(3-trifluoromethyl-2-pyridyl)piperazine,dihydrochloride ##STR21##

A mixture of5-(3-bromo-1-propylidene)-10,11-dihydro-5H-dibenzo[(a,d)]cycloheptene(1.10 g, 3.5 mmol, prepared similarly as described in WO 9518793),1-(3-(trifluoromethyl)-2-pyridyl)piperazine (0.81 g, 3.5 mmol),potassium carbonate (1.45 g, 10.5 mmol) and sodium iodide (0.53 g, 3.5mmol) in dry 2-butanone (10 ml) was heated at reflux temperature for 40h. The solvent was removed in vacuo and the remainder was dissolved intoluene (25 ml) and water (25 ml). The organic layer was separated,dried (MgSO₄) and concentrated in vacuo. The residue was purified byflash chromatography on silica gel using a mixture of toluene and ethylacetate (3:1) containing 2.5% triethylamine as eluent, to give 1.54 g(95 %) of the free base. This was dissolved in tetrahydrofuran (25 ml)and 1 N hydrogen chloride in diethyl ether (7 ml) was added. Theprecipitated solid was isolated by filtration and dried in vacuo to give1.45 g (77%) of the title compound as a solid.

M.p. 225-227° C. Calculated for C₂₈ H₂₈ N₃ F₃ 2 HCl: C, 62.69%; H,5.64%; N, 7.83%; Found: C, 61.99%; H, 5.82%; N, 7.60%.

Example 162-(4-(2-(6,11-Dihydro-dibenzo[b,e]thiepin-11-ylidene)ethyl)piperazin-1-yl)-3-pyridinecarboxylicacid, dihydrochloride ##STR22##

A mixture of 11-(2-bromoethylidene)-6,11-dihydrodibenzo[b,e]thiepine(2.5 g, 7.9 mmol, prepared similarly as described in Coll. Czech. Chem.Comm. 52, 1566 (1987)), ethyl 2-(1-piperazinyl)-3-pyridinecarboxylate(1.86 g, 7.9 mmol), potassium carbonate (1.45 g, 10.5 mmol) andN,N-dimethylformamide (15 ml) was stirred and heated at 150° C. for 10h. The mixture was diluted with water and extracted with benzene (50ml). The organic phase was dried (potassium carbonate), filtered and thesolvent was evaporated in vacuo. The oily residue was purified on silicagel (50 g), using ethyl acetate as eluent to give the base which wasdissolved in diethyl ether and neutralised with oxalic acid in acetone.This afforded 2.7 g (54%) of ethyl 2-(4-(2-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)ethyl)-1-piperazinyl)-3-pyridinecarboxylatehydrogen oxalate hemihydrate.

TLC: R_(f) =0.5 (SiO₂ : chloroform/ethanol/ammonia=40:2:1).

The above ester (2.25 g, 4.77 mmol) was dissolved in ethanol (40 ml) and5 N sodium hydroxide (3 ml) was added. The mixture was stirred at 40° C.for 20 h, ethanol was evaporated in vacuo and water (40 ml) followed byacetic acid (2 ml) were added. The mixture was extracted withdichloromethane (50 ml), the organic phase was dried (MgSO₄) and thesolvent was evaporated in vacuo. The residue was dissolved in acetoneand neutralised with hydrogen chloride in diethyl ether, affording 2.13g(85%) of the title compound as hemihydrate.

M.p. 188-195° C. Calculated for C₂₆ H₂₅ N₃ O₂ S, 0.5 H₂ O, 2 HCl: C,59.42%; H, 5.37%; N, 8.00%; Cl, 13.49%; S, 6.10%; Found: C, 58.94%; H,5.23%; N, 8.10%; Cl, 13.44%; S, 5.80%

Example 172-(4-(3-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylicacid dihydrochloride ##STR23##

A solution of cyclopropylmagnesium bromide in dry tetrahydrofuran(prepared from cyclopropyl bromide (3.7 g, 0.031 mol), magnesiumturnings (0.8 g, 0.033 mol) and dry tetrahydrofuran (50 ml) under anatmosphere of nitrogen) was added dropwise to a solution of(6,11-dihydrodibenzo[b,e]thiepin-11-one (3.5 g, 0.016 mol, similarlyprepared as described in Chem. Pharm. Bull. 39, 1991, 2564) in drytetrahydrofuran (50 ml). When addition was complete, the mixture washeated at 50° C. for 2 h. The reaction mixture was cooled on an ice-bathand saturated ammonium chloride (50 ml) and water (50 ml) were carefullyadded. The mixture was extracted with diethyl ether (2×100 ml), dried(MgSO₄), filtered and the solvent was evaporated in vacuo to give 4.4 gof crude 11-cyclopropyl-6,11-dihydro-11H-dibenzo[b,e]thiepin-11-ol as anoil.

The above crude alcohol (4.0 g) was dissolved in dichloromethane (50 ml)and a solution of trimethylsilyl bromide (2.1 ml, 0.016 mol) was addeddropwise at room temperature. When addition was complete the mixture wasstirred at room temperature for 1.5 h and water (50 ml) was added. Thephases were separated and the organic phase was washed with water (50ml), dried (MgSO₄) and the solvent was evaporated in vacuo to give 4.1 g(83%) of crude1-bromo-3-(6,11-dihydro-dibenzo[b,e]thiepin-11-ylidene)propane as asolid.

TLC: R_(f) =0.55 (SiO₂ : benzene/cyclohexane=1:3).

A mixture of the above bromide (3.65 g, 0.011 mol),2-piperazinyl-3-pyridinecarboxylic acid ethyl ester (3.11 g, 0.0132mol), potassium carbonate (4.55 g, 0.033 mol) and sodium iodide (1.61 g,0.011 mol) in 2-butanone (53 ml) was heated at reflux temperature for 6h. After standing overnight, the reaction mixture was filtered and thefiltrate evaporated in vacuo. The oily residue was purified by columnchromatography on silica gel (70 g) using chloroform as eluent. Thisafforded 4.87 g (91%) of2-(4-(3-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylicacid ethyl ester as an oil.

TLC: R_(f) =0.42 (SiO₂ : ethyl acetate/n-hexane=1:1).

The above ester (2.77 g, 0.0057 mol) was dissolved in ethanol (46 ml)and 4 N sodium hydroxide (6.34 ml, 0.024 mol) was added. The mixture wasleft at room temperature overnight. Concentrated hydrochloric acid (4.76ml) and dichloromethane (300 ml) were added and the organic layer wasseparated, dried (MgSO₄) and evaporated in vacuo. The residue wasstripped with dichloromethane (3×80 ml). After stirring with a mixtureof acetone (100 ml) and diethyl ether (100 ml), 0.75 g (24%) of thetitle compound was obtained.

M.p. 161-166° C. Calculated for C₂₇ H₂₇ N₃ O₂ S, 2 HCl, H₂ O: C, 59.12%;H, 5.70%; N, 7.66%; S, 5.85%; Found: C, 59.27%; H, 5.61%; N, 7.54%; S,6.13%.

Example 182-(4-(2-(6,11-Dihydrodibenzo[b,e]thiepin-11-yloxy)ethyl)-1-piperazinyl)-3-pyridinecarboxylicacid ##STR24##

6,11-Dihydrodibenzo(b,e)thiepin-11-ol (13.2 g, 0.0578 mol, preparedsimilarly as described in Ceskoslov. Farm. 11, 404 (1962)) was dissolvedin benzene (160 ml) and 2-bromoethanol (10.8 g, 0.086 mol) andconcentrated sulphuric acid (2 ml) were added. The mixture was stirredat ambient temperature for 2 h and after standing overnight ice-waterwas added and the phases were separated. The organic phase was washedwith 5% sodium bicarbonate, dried (MgSO₄) and the solvent was evaporatedin vacuo affording a residue which was crystallized from a mixture ofbenzene and cyclohexane. This afforded 13.5 g (70%) of11-(2-bromethoxy)-6,11-dihydrodibenzo[b,e]thiepine as a solid.

TLC: R_(f) =0.08 (SiO₂ : cyclohexane/ethyl acetate=5:1).

A mixture of the above bromide (2.85 g, 8.5 mmol), ethyl2-(1-piperazinyl)-3-pyridinecarboxylate (2.0 g, 8.5 mmol), potassiumcarbonate (1.65 g, 12 mmol) and N,N-dimethylformamide (15 ml) wasstirred and heated at 150° C. for 10 h. The mixture was diluted withwater and extracted with benzene (50 ml). The organic phase was dried(potassium carbonate), filtered and the solvent was evaporated in vacuo.The oily residue was purified on silica gel (50 g), using ethyl acetateas eluent to give the free base which was dissolved in diethyl ether andneutralised with oxalic acid in acetone, affording 3.75 g (74%) of ethyl2-(4-(6,11-dihydrodibenzo[b,e]thiepin-11-yloxyethyl)-1-piperazinyl)-3-pyridinecarboxylatehydrogen oxalate hydrate was obtained as crystals. The free base wasreleased from the above oxalate with aqueous ammonia and isolated byextraction with diethyl ether.

TLC: R_(f) =0.55 (SiO₂ : chloroform/ethanol/ammonia=40:2:1).

The above free ester (2.65 g, 5.4 mmol) was dissolved in ethanol (40 ml)and 5 N sodium hydroxide (4 ml) was added. The mixture was stirred at40° C. for 20 h, ethanol was evaporated in vacuo, and water (40 ml)followed by acetic acid (3 ml) were added. The mixture was extractedwith dichloromethane (50 ml). The product crystallizing from thissolution was filtered off. Dichloromethane was evaporated from themother liquor and the second crop of the product was obtained bytrituration with acetone, yielding a total amount of 2.4 g (95%) of thetitle compound.

M.p. 217-218.5° C. Calculated for C₂₆ H₂₇ N₃ O₃ S, 0.25 H₂ O: C, 67.00%;H, 5.95%; N, 9.02%; S, 6.88%; Found: C, 67.18%; H, 5.84%; N, 8.99%; S,6.64%.

Example 196-(4-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)piperazin-1-yl)-2-pyridinecarboxylicacid hydrochloride ##STR25##

To a solution of 6-piperazinyl-2-pyridine carboxylic acid ethyl ester(7.0 g, 0.03 mol) in 2-butanone (150 ml),3-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yliden1)-1-propylmethanesulfonate (6.8 g, 0.0207 mol) and potassium carbonate (8.0 g)were added. The reaction mixture was heated at 40° C. for 3 h. Afterstanding overnight at room temperature, heating was continued at 60° C.for 9 h and at reflux temperature for 9 h. The solid was filtered off,washed with acetone and the filtrate was evaporated in vacuo. Theresidue was purified by column chromatography on silica gel (200 g)using chloroform as eluent. This afforded 6.63 g (68%) of6-(4-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)piperazin-1-yl)-2-pyridinecarboxylicacid ethyl ester as an oil.

TLC: R_(f) =0.32 (SiO₂ : petroleum ether/ethyl acetate=3:2).

To a solution of the above ester (3.74 g, 8.0 mmol) in ethanol (38 ml),a solution of sodium hydroxide (1.3 g) in water (4.9 ml) was added andthe reaction mixture was left at room temperature for 60 h. Concentratedhydrochloric acid (4.9 ml) was added followed by dichloromethane (230ml). The mixture was stirred for 5 minutes, the phases were separatedand the organic phase dried (MgSO₄) and evaporated in vacuo. The foamyresidue was dissolved in acetone (500 ml) and evaporated to one third ofits volume. The formed solid was filtered off, yielding 1.8 g (47%) ofthe title compound.

M.p. 233-243° C. Calculated for C₂₈ H₂₉ N₃ O₂, HCl, 0.25 H₂ O: C,69.98%, H, 6.40%, Cl, 8.74%, N, 7.38%, Found: C, 69.90%, H, 6.42%, Cl,8.47%, N, 7.52%.

Example 202-(4-(3-(3-Methyl-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylicacid hydrochloride ##STR26##

Under nitrogen and with magnetic stirring on an oil bath, sodium (3.14g, 0.136 mol) was heated at 120-130° C. until melted and then methanol(6.1 ml, 0.15 mol) was added dropwise. As some unreacted sodiumremained, additional methanol (1 ml) was added. At the same temperature,the alcoholate was heated for 1 h and the white loose solid was cooledon ice-salt bath and at 10-15° C. A mixture of diethyl2-bromophenylmethylphosphonate (27.94 g, 0.091 mol) and4-methyl-2-nitrobenzaldehyde (15.02 g, 0.091 mol, prepared similarly asdescribed in Zh.Org.Khim.1968, 5, 953 or in Ann.1956, 627, 218) inN,N-dimethylformamide (60 ml) was added dropwise. When the addition wascomplete, the reaction mixture was stirred for additional 20 minutes atthe same temperature, maintained at room temperature under light coolingon a water bath for additional 1 h and left to stand overnight in therefrigerator. Water (150 ml) was added under cooling on an ice bath, thereaction mixture was diluted with additional water (450 ml) andextracted with ethyl acetate (5×100 ml). The organic layer was washedwith water (100 ml) and dried (MgSO₄). The residue (32.5 g) was stirredwith cyclohexane, the solid was filtered off, dissolved in warmcyclohexane, and the hot solution was decanted from the oil whichseparated on the flask, and cooled. The precipitated solid was filteredoff, washed with cyclohexane and dried (8.9 g) (product A). The filtratewas combined with the previously separated oil, the mixture wasevaporated in vacuo and the residue (19.25 g) was purified by columnchromatography on silica gel (200 g) using a mixture of cyclohexane andbenzene (10:1) as eluent, which afforded 1,2-bis(2-bromophenyl)ethylene(3.26 g, 21%) as a by-product.

Change of the eluent to a mixture of cyclohexane and benzene (1:1)afforded an additional portion (6.70 g) of solid, which was identicalwith product A isolated above from the reaction mixture (cyclohexane),giving a total yield of 13.60 g (29%) ofZ-(2-(2-bromophenyl)vinyl)-4-methyl-2-nitrobenzene.

TLC: R_(f) =0.75 (SiO₂ : cyclohexane/ethyl acetate=5:1).

A solution of the above nitrobenzene (9.68 g, 30.3 mmol) in ethanol (110ml) and methanol (40 ml) was hydrogenated 2 h at 3 MPa in the presenceof morpholine (0.6 ml) and Rh/C (KO 319) catalyst (2 g). The catalystwas filtered off, the filtrate evaporated in vacuo and the residue wasstripped with toluene (3×20 ml). The oily residue crystallized afterstanding at room temperature. After washing the solid with petroleumether and drying, 2-(2-(2-bromophenyl)ethyl)-5-methylaniline (8.15 g,92%) was obtained.

M.p. 67-69° C. Calculated for C₁₅ H₁₆ BrN: C, 62.08%; H, 5.56%; Br,27.54%; N, 4.83%; Found: C, 62.45%; H, 5.70%; Br, 27.25%; N, 5.06%.

A mixture of above amine (10.4 g, 0.036 mol) and sodium formate (4.9 g,0.072 mol) in formic acid (70 ml) was heated at reflux temperature for 3h and left to stand overnight. The reaction mixture was poured intowater (500 ml) and stirred for 30 minutes. The solid was filtered off,washed with water and subsequently with ethanol. After drying in air,N-(2-(2-(2-bromophenyl)ethyl)-5-methylphenyl)formamide (8.3 g, 72%)wasobtained.

M.p. 167-169° C.

A mixture of the above formyl derivative (6.50 g, 20 mmol), potassiumcarbonate (3.39 g, 24 mmol), copper (0.81 g, 13 mmol) and copper (I)bromide (1.02 g, 7 mmol) in dimethyl sulfoxide (40 ml) was heated to160° C., cooled, 20% sodium hydroxide (4 ml) was added and the mixturewas heated to 75° C. for 30 minutes. The mixture was poured into water(400 ml) and ethyl acetate (500 ml), the solid was filtered off, theorganic layer was separated, washed with 1 N hydrochloric acid, 10%sodium hydrogen carbonate and water (2×100 ml) and dried (MgSO₄). Theresidue (4.88 g) was purified by column chromatography on silica gelusing a mixture ofcyclohexane and benzene (1:1) as eluent. This afforded2.26 g (54%) of 3-methyl-10,11-dihydro-5H-dibenzo[b,f]azepine.

TLC: R_(f) =0.75 (SiO₂ : cyclohexane/ethyl acetate=5:1).

To a solution of the above azepine (2.09 g, 0.01 mol) in benzene (25 ml)a suspension of sodium amide (1.01 g, 0.013 mol, 50% suspension intoluene diluted with 5 ml of benzene) was added and the mixture washeated to 70° C. for 1.5 h under a nitrogen atmosphere. Then1-tetrahydropyranyl-3-bromopropanol (2.90 g, 0.013 mol) was added andthe mixture was heated to 70° C. for 19 h. After cooling, the reactionwas quenched with water (20 ml), benzene was added (10 ml), the layerswere separated and the organic layer was dried (MgSO₄). The residue(3.73 g) was dissolved in methanol (20 ml), 6 N hydrochloric acid (6 ml)was added and the mixture was heated at reflux temperature for 30 min.Then the methanol was evaporated in vacuo, the residue was treated withbenzene (20 ml) and water (10 ml), the aqueous layer washed once morewith benzene (10 ml) and the combined benzene extracts were dried(MgSO₄). The solvent was evaporated in vacuo and the residue (2.65 g)was purified by column chromatography on silica gel (50 g) using amixture of benzene and ethyl acetate (10:1) as eluent. This afforded1.83 g (68%) of5-(3-hydroxypropyl)-3-methyl-10,11-dihydro-5H-dibenzo[b,f]azepine as anoil.

TLC: R_(f) =0.25 (SiO₂ : chloroform).

To a solution of the above alcohol (1.70 g, 6.3 mmol) and triethylamine(1.9 g, 18 mmol) in benzene, (25 ml) a solution of methanesulfonylchloride (0.91 g, 7.9 mmol) in benzene (8 ml) was added dropwise over 15minutes at 18-20° C. under cooling on an ice bath. The reaction mixturewas stirred at room temperature for 2 h. Separated triethylaminehydrochloride was filtered off, washed with benzene (15 ml), thecombined benzene layers were washed with water (2×25 ml) followed bybrine (20 ml) and dried (MgSO₄). After evaporation of the solvent invacuo the oily methanesulfonate (2.07 g, 94%) was used in the next stepwithout further purification.

TLC: R_(f) =0.50 (SiO₂ : chloroform).

A mixture of the above methanesulfonate (2.07 g, 6 mmol), ethyl2-(1-piperazinyl)-3-pyridinecarboxylate (1.41 g, 6 mmol), potassiumiodide (1.00 g, 6 mmol) and potassium carbonate (2.49 g, 18 mmol) in2-butanone (40 ml) was heated at reflux temperature for 7 h. The mixturewas cooled, water (75 ml) and ether (75 ml) were added, the organicphase was washed with water (20 ml) and dried (MgSO₄). The solvent wasremoved in vacuo, affording the ethyl ester of the title compound (3.07g) as an oil.

TLC: R_(f) =0.35 (SiO₂ : ammonia saturated chloroform/ethanol=50:1).

To a solution of the above crude ester (2.90 g) in 2-propanol (15 ml) asolution of oxalic acid dihydrate (0.85 g) in 2-propanol (5 ml) wasadded, the mixture was gently warmed and then cooled. The separated saltwas filtered off, washed with additional 2-propanol and ether and driedin vacuo affording 2.97g (83%) of2-(4-(3-(3-methyl-10,11-dihydro-5H-dibenzo-[b,f]azepin-5-yl)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylic acid ethyl ester oxalate.

From the above oxalate (2.85 g) the free ester (1.91 g) was liberated ina dichloromethane suspension with ammonium hydroxide and obtained as anoil.

To a solution of above ester (1.83 g, 3.8 mmol) in ethanol (22 ml), 20%sodium hydroxide (2.5 ml) was added and the mixture was stirred for 5 hat room temperature. The main portion of ethanol was removed in vacuo,the residue dissolved in dichloromethane (180 ml) and acidified with 2 Nhydrochloric acid, the aqueous layer was separated, the organic layerwas washed with water (10 ml), dried (MgSO₄) and the solvent was removedin vacuo. The foamy residue was evaporated with acetone (3×20 ml) andthe amorphous solid (1.81 g ) was dissolved in acetone. The crystalline,in acetone insoluble title compound precipitated from the solution andwas obtained by filtration. (1.26 g, 67%).

M.p. 200-206° C. Calculated for C₂₈ H₃₂ N₄ O₂, HCl: C, 68.21%; H, 6.75%;Cl, 7.19%; N, 11.36%; Found: C, 68.05%; H, 6.83%; Cl, 7.28%; N, 10.95%.

Example 216-(4-(3-(Dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)-piperazin-1-yl)-pyridine-2carboxylicacid hydrochloride ##STR27##

12H-Dibenzo[d,g][1,3,6]dioxazocine (1.7 g, 8 mmol, similarly prepared asdescribed in EXAMPLE 3) was dissolved in dry benzene (25 ml) at 45° C.In a nitrogen atmosphere, a suspension of sodium amide in toluene (1.1g, 50%, 14 mmol) was added and the mixture was stirred at 70° C. for 2.5h. Freshly distilled 1-tetrahydropyranyloxy-3-bromopropane (2.88 g, 13mmol, 72° C./70 Pa) was added and the mixture was heated at refluxtemperature for 14 h and left overnight at room temperature. Benzene (25ml) and water (25 ml) were added to the reaction mixture, stirred for 15min and separated. The organic extract was dried (sodium sulfate) andthe solvent evaporated in vacuo. The residue (4.9 g) was dissolved inmethanol (20 ml), 6 N hydrochloric acid (6.7 ml, 40 mmol) was added, themixture was stirred at 22° C. for 40 minutes and alkalised with 2 Nsodium carbonate (20 ml). The product was extracted with benzene (80ml), the organic phase washed with water (30 ml, dried (sodium sulfate)and evaporated in vacuo (3.5 g). The raw product was purified bychromatography on silica gel (80 g), using a mixture of benzene andethylacetate (10:1) as eluent.12-(3-Hydroxypropyl)dibenzo[d,g][1,3,6]dioxazocine (1.36 g, 47%) wasobtained as an oil.

TLC: R_(f) =0.45 (SiO₂ : benzenelethyl acetate=10:1).

A solution of methanesulfonyl chloride (0.98 g, 8.6 mmol) in dry toluene(10 ml) was added dropwise to a stirred solution of the above propanolderivative (1.36 g, 5 mmol) and triethylamine (1.6 g, 15 mmol) in drytoluene (40 ml), under a nitrogen atmosphere, over 20 minutes at ambienttemperature. A slightly exothermic reaction occurred. The reactionmixture was stirred at 24° C. for 3 h and then at 36° C. for 1.5 h. Thereaction mixture was diluted with toluene (50 ml), washed with water(4×30 ml) and brine (25 ml), dried (sodium sulfate) and evaporated invacuo. The oily mesylate (1.8 g, 100%) was used for the next stepwithout further purification.

TLC: R_(f) =0.36 (SiO₂ : benzene/ethyl acetate=10:1).

The above mesylate (1.8 g, 5 mmol), ethyl6-(piperazin-1-yl)pyridine-2-carboxylate (1.9 g, 8 mmol), dry potassiumcarbonate (1.6 g, 12 mmol) and potassium iodide (0.15 g, 1 mmol) in dryacetone (30 ml) and N,N-dimethylformamide (10 ml) was stirred at refluxtemperature for 5 h. Acetone was distilled off, the residue wasdissolved in benzene (150 ml) and washed with water (4×50 ml) and brine(30 ml), dried (sodium sulfate) and evaporated in vacuo. The oilyresidue (3.54 g) was purified by chromatography on silica gel (70 g),using first benzene and then ethyl acetate as eluents). This providedthe ethyl ester of the title compound (1.44 g, 59%) as an oil.

TLC: R_(f) =0.62 (SiO₂ : benzene/ethyl acetate=10:1).

A solution of the above ethyl ester (1.44 g, 2.95 mmol) in ethanol (15ml) and 5 N sodium hydroxide (20 ml) was stirred 15 minutes at 50-55° C.and then 21 h at 22° C., dichloromethane (200 ml) was added and themixture was acidified to pH 1 with 2.5 N hydrochloric acid. The organiclayer was separated, dried (sodium sulfate) and evaporated in vacuo toobtain 1.14 g of a solid residue, which was triturated with a mixture ofacetone(15 ml) and ether (20 ml). The product was filtered off andwashed with acetone-ether (2:3, 3×10 ml) and ether (5 ml) to yield 0.9 g(79%) of the title compound.

M.p. 224-227° C. Calculated for C₂₆ H₂₉ N₄ O₄, HCl, 0.5 H₂ O: C, 61.71%;H, 5.98%; N, 11.07%; Found: C, 61.60%; H, 6.05%; N, 10.79%.

What is claimed is:
 1. A compound of formula I ##STR28## wherein R¹ andR² independently are hydrogen, halogen, trifluoromethyl, hydroxy, C₁₋₆-alkyl orC₁₋₆ -alkoxy; and X is --OCH₂ O--; and Y is >N--CH₂ -- whereinonly the underscored atom participates in the ring system; and r is 1,2or 3; and Z is selected from ##STR29## wherein M₁, and M₂ independentlyare CH or N; and R⁵ is hydrogen, C₁₋₆ -alkyl, phenyl or benzyl; andR³ ishydrogen, halogen, trifluoromethyl, nitro or cyano; and R⁴ is hydrogen,halogen, trifluoromethyl, nitro, cyano, (CH₂)_(m) COR¹¹, (CH₂)_(m) OH or(CH₂)_(m) SO₂ R¹¹ wherein R¹¹ is hydroxy, C₁₋₆ -alkoxy or NHR¹², whereinR¹² is hydrogen or C₁₋₆ -alkyl; and m is 0, 1 or 2; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 wherein R¹ and R² independently are hydrogen, halogen,trifluoromethyl or C₁₋₆ -alkyl.
 3. A compound according to claim 1wherein r is 1 or
 2. 4. A compound according claim 1 wherein Z isselected from ##STR30## wherein M₁ and M₂ independently are CH or N. 5.A compound according to claim 1 wherein R³ is hydrogen, trifluoromethyl,nitro or cyano.
 6. A compound according to claim 1 wherein R⁴ ishydrogen, trifluoromethyl, nitro, cyano or (CH₂)_(m) COR¹¹.
 7. Acompound according to claim 1 wherein m is 0 or
 1. 8. A compoundaccording to claim 1 wherein R¹¹ is hydroxy.
 9. A compound according toclaim 1 selected from thefollowing:2-(4-(3-(12H-Dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)piperazin-1-yl)-3-pyridinecarboxylicacid;2-(4-(3-(2-Chloro-12H-dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)-piperazin-1-yl)-3-pyridinecarboxylicacid; and6-(4-(3-(Dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)-piperazin-1-yl)-pyridine-2-carboxylicacid; or a pharmaceutically acceptable salt thereof.
 10. A method ofpreparing a compound according to claim 1, comprisinga) reacting acompound of formula II ##STR31## wherein R¹, R², X, Y, and r are asdefined in claim 1 and W is a suitable leaving group with a compound offormula III ##STR32## wherein Z is as defined in claim 1 to form acompound of formula I.
 11. A pharmaceutical composition comprising as anactive component an effective amount of a compound according to claim 1together with a pharmaceutically acceptable carrier or diluent.
 12. Thepharmaceutical composition according to claim 11 comprising between 0.5mg and 1000 mg of the compound.
 13. A method of treating neurogenicinflammation comprising administering to a subject in need thereof aneffective amount of a compound according to claim
 1. 14. A method oftreating neurogenic inflammation comprising administering to a subjectin need thereof a pharmaceutical composition according to claim
 11. 15.A method of treating neurogenic inflammation associated with neuropathy,rheumatoid arthritis, migraine or itching comprising administering to asubject in need thereof an effective amount of a compound of claim 1.16. A method of treating neurogenic inflammation associated withneuropathy, rheumatoid arthritis, migraine or itching comprisingadministering to a subject in need thereof a pharmaceutical compositionof claim
 11. 17. A method of treating insulin resistance innon-insulin-dependent diabetes mellitus (NIDDM) or ageing-associatedobesity comprising administering to a subject in need thereof aneffective amount of a compound of claim
 1. 18. A method of treatinginsulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) orageing-associated obesity comprising administering to a subject in needthereof a pharmaceutical composition of claim 11.